Method Of Making An L-Menthol Dosage Form

ABSTRACT

A method of making an L-menthol dosage form includes forming a wet granulation including an L-menthol source and at least one pharmaceutical excipient. The wet granulation is extruded into an extrudate and the extrudate is cut into individual core pieces. The individual core pieces are spheronized into individual spheronized cores and the individual spheronized cores are dried to form dried individual spheronized cores. The dried individual spheronized cores are spray coated with a liquid proteinaceous material that forms a film of a proteinaceous material over the dried individual spheronized cores. The film of proteinaceous material is dried over the dried individual spheronized cores to form individual subcoated cores. An enteric coating is applied and dried over the individual subcoated cores to form a plurality of individual enteric coated cores.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 14/876,465, filed Oct. 6,2015, which is a continuation of application Ser. No. 14/524,326, nowU.S. Pat. No. 9,192,583, filed Oct. 27, 2014, which is continuation ofapplication Ser. No. 14/033,713, now U.S. Pat. No. 8,895,086, filed Sep.23, 2013, which claims priority to U.S. provisional application61/815,073, filed Apr. 23, 2013 and U.S. provisional application61/880,294, filed Sep. 20, 2013. These priority applications areincorporated by reference herein in their entirety.

FIELD

This relates to therapeutic L-menthol compositions, and, moreparticularly, to L-menthol compositions with enhanced storage stability.

BACKGROUND

Terpenes are a large class of organic compounds that are often naturallyproduced by plants and provide the fragrant aroma of plant-derivedessential oils. Many terpenes and their associated essential oils arewidely known to be pharmaceutically active. Because of this, people havedeveloped various ways of administering terpenes to treat many differentailments.

By way of example, peppermint oil is widely used to addressgastrointestinal problems such as irritable bowel syndrome because itinhibits the smooth muscles in the gastrointestinal tract fromcontracting. Unfortunately, however, if peppermint oil is released inthe stomach, it is absorbed quickly and can upset the stomach. Toovercome this problem, others have developed oral delayed-releasepeppermint oil formulations that allow the peppermint oil to pass intothe intestines before it is released.

A common method for delivering peppermint oil to the intestines is toload a hollow capsule with peppermint oil and coat the capsule with anenteric coating. The enteric coating prevents the capsule fromdissolving in the stomach and releasing the peppermint oil too early.

These single-unit enteric coated capsules have several drawbacks,including extremely variable gastric emptying time (from 60 to 570minutes), dose dumping, and their inability to exit from the contractedpylorus due to the presence of food in the stomach. These problems canbe addressed by developing multiparticulate compositions containingterpene-based active ingredients. In U.S. patent publication2012/0207842 and corresponding WIPO publication WO 2012/109216, wedescribed a multiparticulate formulation containing high-purityL-menthol. Some of the particulates in those formulations included acore containing L-menthol, a subcoating over the core, and an entericcoating over the subcoated core. The preferred subcoating was hydroxylpropyl methyl cellulose or “HPMC.” The multiparticulate formulationsdescribed in that application provided the release profile that wedesired and worked well for some applications, but are not optimized forall applications. U.S. patent publication 2012/0207842 and WIPOpublication WO 2012/109216 are both incorporated by reference in theirentireties.

We found that it is difficult to make multiparticulate formulationscontaining terpene-based active ingredients because terpenes are veryvolatile. If the multiparticulate core containing terpene-based activeingredients is heated or stored for extended periods, much above roomtemperature, the terpenes will permeate, evaporate or sublimate andleave the core. This made processing the cores very difficult,especially when it came time to cure the enteric coating on the cores atelevated temperatures. For our L-menthol formulations, we resorted tolow temperature processing techniques.

SUMMARY

Through extensive research, we discovered that using a proteinaceouscoating prevents the L-menthol based active ingredients in the core frompermeating, evaporating, or sublimating at elevated temperatures and forlong periods of time. Accordingly, we have invented new compositionscontaining terpene-based active ingredients that have enhanced storagestability.

A multiparticulate composition embodying the principles of the inventioncomprises a plurality of individual enteric coated cores containing oneor more terpene-based active ingredients and having a continuousproteinaceous subcoating layer covering the individual cores andseparating the individual cores from their respective enteric coatings.

Some preferred terpene-based active ingredients includeterpene-containing essential oils such as peppermint oil and carawayoil, and/or L-menthol. These ingredients may be used alone incombination with each other. For example, the composition may include:(i) a mixture of peppermint oil and caraway oil or (ii) L-menthol froman at least 80% pure L-menthol source dissolved in caraway oil.

Preferably, but not necessarily, the enteric coated cores are spheroidaland are not more than 3 mm in diameter.

In a particularly preferred example of the multiparticulate composition,the cores comprises about 10% w/w to about 35% w/w of the one or moreterpene-based active ingredients, about 40% w/w to about 75% w/wmicrocrystalline cellulose, and about 2% w/w to about 10% w/w methylcellulose; the subcoating comprises about 3.5% w/w to about 40% w/w ofthe enteric coated cores; and the enteric coating comprises about 2% toabout 35% w/w of the enteric coated cores.

The proteinaceous subcoating may comprise a continuous gelatin, casein,whey proteins or isolated vegetable protein film adhered to the coreand/or may be a dried proteinaceous gel. The continuous proteinaceoussubcoating layer covering the core is adapted to prevent the one or moreterpene-based active ingredients from mixing with the enteric coating.

The enteric coating may have a glass transition temperature higher thana standard boiling point or sublimation point of the one or moreterpene-based active ingredients.

Another aspect of the invention is a method of making the enteric coatedmultiparticulate composition. In general, the method comprises coating acore containing one or more pharmaceutically active terpene-based activeingredients with a liquid proteinaceous material, drying the liquidproteinaceous material on the core to form a subcoated core, andapplying an enteric coating over the subcoated core.

The proteinaceous subcoating material may be gelatin and the liquidproteinaceous material may be a solution containing at least about 35%gelatin.

A preferred technique for coating the core is to spray the liquidproteinaceous material onto the core.

The core may be prepared by blending the one or more pharmaceuticallyactive terpene-containing substances with water and pharmaceuticallyacceptable excipients to form a wet mass, extruding the wet mass,spheronizing the extruded wet mass, and drying the resulting spheronizedpieces.

In the method, the one or more pharmaceutically active terpene-basedactive ingredients include terpene-containing essential oils and/orL-menthol. Particularly preferred terpene-based active ingredients areselected from peppermint oil, caraway oil, L-menthol, or a combinationthereof. In one example, the one or more terpene-based activeingredients include peppermint oil and/or L-menthol. In another example,the one or more terpene-based active ingredients include a mixture ofpeppermint oil and caraway oil. In yet another example, the one or moreterpene-based active ingredients include L-menthol and caraway oil, theL-menthol being from an at least 80% pure L-menthol source.

Applying the enteric coating over the subcoated core may include heatingthe enteric coated core to at least a glass transition temperature ofthe enteric coating without releasing the one or more terpene-basedactive ingredients from the core.

The method is preferably, but not necessarily, used to make entericcoated cores that are spheroidal and not more than 3 mm in diameter.

Yet another aspect of the invention is a method of treating agastrointestinal disorder in a subject. The method comprisesadministering to the subject a multiparticulate composition having aplurality of individual enteric coated cores containing one or moreterpene-based active ingredients and a continuous proteinaceoussubcoating layer covering the core and separating the core from theenteric coating. The multiparticulate composition used in this methodmay include any of the features and ingredients described in thisdisclosure.

Preferred techniques for administering the composition include enteraladministration. If desired, the multiparticulate composition may beblended with an acidic vehicle prior to being administered.

These and other aspects, embodiments, and advantages will be betterunderstood by reviewing the accompanying figures and the DetailedDescription of Embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of an accelerated stability assayfor a multiparticulate composition according to an embodiment stored at40 degrees C. and 75% relative humidity for four weeks; and

FIG. 2 is a graph showing the results of a two-stage dissolution testfor a multiparticulate composition according to an embodiment after thecomposition was stored at 40 degrees C. and 75% relative humidity.

DETAILED DESCRIPTION OF EMBODIMENTS

In the Summary and Detailed Description of Embodiments reference is madeto particular features including method steps. It is to be understoodthat the disclosure of the in this specification includes all possiblecombinations of such particular features, even if those combinations arenot explicitly disclosed together. For example, where a particularfeature is disclosed in the context of a particular aspect orembodiment, that feature can also be used, to the extent possible, incombination with and/or in the context of other particular aspects andembodiments

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, embodiments will be described more fully. Theembodiments may, however, take in many different forms and should not beconstrued as limited to the embodiments set forth herein.

A multiparticulate composition aspect is first described. Themultiparticulate composition is adapted to carry biologically activeingredients to the intestines (duodenum, small intestine, or colon) andincludes a plurality of particulates that are preferably spheroidal inshape and are sized to fit through the pyloric sphincter when it is in arelaxed state. The diameter of each particulate is preferably in therange of about 0.1 mm to about 3 mm or, about 1 mm to about 2.5 mm, orless than about 1.4 mm.

The particulates are preferably formed from a spheroidal core that iscoated with several coating layers, including a subcoating and anenteric coating. The subcoating encompasses the core and physicallyseparates the core from the enteric coating. The enteric coating ispositioned about the subcoating in such a way that the subcoating islocated between the core and enteric coating. The particulates may alsoinclude one or more additional coatings such as a sealant coating,finish coating, or a color coating on the enteric coating.

The core contains the primary active ingredient(s), which areterpene-based substances such as terpenes, terpenoids, and/or one ormore essential oils. The core may also contain secondary activeingredients such as one or more other terpenes, terpenoids, and/oressential oils. Terpene-based substances that may be used as secondaryactive ingredients include but are not limited to caraway oil, orangeoil, ginger oil, turmeric oil, curcumin oil, and fennel oil, amongothers.

One of the preferred terpene-based active ingredients is L-menthol froman L-menthol source that is at least about 80% pure L-menthol, such asliquid, solid, or crystalline L-menthol. L-menthol is typically acrystalline material at room temperature, has a melting point atstandard pressure of about 42θ-45° C., and may undergo sublimation atslightly above room temperature. The 80% pure L-menthol may be dissolvedin an essential oil such as caraway oil to form a liquid mixture, priorto mixing with acceptable excipients and water to make a wet mass whilethe cores are being formed.

The term “solid L-menthol” means L-menthol in its solid form, preferablyin its crystalline form. In the crystalline form, L-menthol issubstantially free of undesirable impurities. Although it may not alwaysbe necessary, it is preferred that the starting material for L-mentholappear as visually perceptible L-menthol crystals that are then groundinto a polycrystalline powder. Micronizing the L-menthol is oftenadvantageous because doing so produces more L-menthol surface area,which improves L-menthol's aqueous solubility. It is preferred, however,that the L-menthol be micronized without raising the temperature of theL-menthol enough to degrade the L-menthol molecules, cause L-menthol tomelt, or cause L-menthol to sublimate. A suitable technique forproducing micronized L-menthol crystals involves jet milling.

Essential oils such as peppermint oil, caraway oil, orange oil, fenneloil etc. are liquid at room temperature. They are usually formulated asliquids in a capsule, with an enteric-coating over the capsule. Wediscovered that essential oils can be mixed with a cellulosic filler anda binder to make a dough or wet mass, but the dough formed by simplymixing these materials together does not produce a core with the desiredstrength for subcoating and further processing. By adding water to thewet mass, we produced cores containing terpene-based activeingredient(s) that were robust enough for subsequent processing.

The core may also contain one or more antioxidants that can maintain thepurity of the terpene-based active ingredients. This is useful when theterpene-based active ingredients that are employed can oxidize to formundesirable derivatives. Examples of antioxidants that may be usedinclude, but are not limited to tocopherol (vitamin E) BHT (butylatedhydroxy toluene), BHA (butylayted hydroxy anisole), and ascorbic acid.

The core may also contain other non-terpene active ingredients such asplant based polyphenolic compounds, including, for example, green teaextract, aloe vera.

The core may also include other active ingredients that behavesynergistically with certain terpenes, such as L-menthol, to treatgastrointestinal disorders. These other active ingredients include drugstypically used to treat various gastrointestinal issues including protonpump inhibitors, anti-inflammatories, and immune suppressors. CombiningL-menthol with these other active ingredients improves their efficacybecause L-menthol enhances their permeation into the intestinal walls.

Examples of PPIs include, but are not limited to omeprazole,lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole,and ilaprazole. Including a PPI is preferred when the L-menthol in thecore is dissolved in caraway oil.

Examples of anti-inflammatory drugs include aminosalicylates, including5-aminosalicylate (5-ASA). Examples of 5-ASA are sulfasalazine,mesalamine, olsalazine and balsalazide. These work by decreasing theinflammation at the level of the lining of the gastrointestinal tract.However they do not address the pain and other symptoms associated withulcerative colitis or Crohn's disease. The 5-ASAs are poorly absorbed.They are more effective when they are released and locally delivered tothe ileum (for Crohn's disease) or colon (for ulcerative colitis). TheL-menthol in combination with aminosalicylates (in the core) and with anenteric coat specific for delivery at the appropriate pH between pH 6.8and 7.5 is useful for treating gastrointestinal disorders. We expectthis combination to address the needs of the patients with the abovedisorders. Enteric coatings suited to these PPI-containing formulationsinclude hypromellose acetate succinate coatings such as AQOAT AS-HF,AQOAT AS-HG and poly(meth)acrylate-based coatings such as EUDRAGIT FS30D or EUDRAGIT S-10.

Examples of immune suppressors include corticosteroids such asprednisone and methylprednisolone. Corticosteroids non-specificallysuppress the immune response. These drugs have significant short- andlong-term side effects. They need to be delivered to the ileum (forCrohn's disease) or colon (for ulcerative colitis) for maximum efficacy.A combination of L-menthol with prednisone, prednisolone ormethylprednisolone, formulated in the core, with an enteric coatspecific for delivery at the appropriate pH between pH 6.8 and 7.5 isuseful for treating gastrointestinal disorders, such as ulcerativecolitis or crohn's disease. This activity may allow the patient toreceive a lower dose of the corticosteroid in combination with L-mentholas compared to the corticosteroid by itself. The unique activities ofL-menthol help relieve abdominal pain, cramps, and diarrhea. Entericcoatings suitable for these immune suppressor-containing formulationsinclude AQOAT AS-HF, AQOAT AS-HG, EUDRAGIT FS 30D or EUDRAGIT S-100.

The core may also include pharmaceutically acceptable fillers,stabilizers, binders, surfactants, processing aids, and/ordisintegrants. By way of example only, suitable materials for performingthese functions are provided.

Preferred fillers include cellulosic filler materials such asmicrocrystalline cellulose, dibasic calcium phosphate, and/or anotherpharmaceutically acceptable filler.

Preferred binders include cellulosic water soluble polymers such asmethyl cellulose, starch, hydroxypropyl cellulose, gelatin,polyvinylpyrrolidone, polyethylene glycol, and/or anotherpharmaceutically acceptable binder.

Because some terpene-based active ingredients, such as L-menthol, arenot very water soluble, it may be advantageous to include a surfactantas a solubilizing agent. Preferred solubulizing agents include but arenot limited to polysorbate 80 and/or sodium lauryl sulfate.Advantageously when polysorbate 80 is used, it may also enhanceabsorption of terpene-based active ingredients into the plasma.

Suitable processing aids include pharmaceutically acceptable processingaids for improving the flowability of the core materials duringprocessing. Preferred processing aids include, but are not limited to,colloidal silicon dioxide, talc, magnesium stearate, stearin, and/oranother pharmaceutically acceptable processing aid.

Preferred disintegrants include, but are not limited to, croscarmellosesodium, polyvinylpyrrolidone (crospovidone) sodium starch glycolate,and/or another pharmaceutically acceptable processing aid. A preferredamount of disintegrant is about 0.05% w/w to about 20% w/w of theenteric coated cores.

In a particularly preferred embodiment of the multiparticulatecomposition, the core comprises about 10% w/w to about 35% w/w of one ormore terpene-based active ingredients; about 25% w/w to about 75% w/wfiller; and about 1.5% w/w to about 10% w/w binder. Here the % w/w isthe weight of the active ingredient or excipient relative to the totalweight of the enteric coated multiparticulates.

Once the core is formed, the subcoating is applied along its exteriorsurface to form a substantially continuous thin film that forms abarrier between the core and the enteric coating that is applied afterthe subcoating. One of the particularly advantageous features is the useof a proteinaceous material as a subcoating material. Examples ofproteinaceous materials that may be used include proteins such as, butnot limited to casein, whey protein, soy protein, and various types ofgelatin (Type A, Type B or derivatives of gelatin) or proteinaceousmaterials that have protein-like structures. In a preferred embodiment,the material used to form the subcoating is a solution containing atleast about 50% of the proteinaceous material dispersed in a solvent.The solvent is preferably, but not necessarily water. A particularlypreferred proteinaceous material is Type A gelatin.

The proteinaceous subcoating is preferably applied to the core in liquidform and subsequently dried on the core. When dry, the subcoatingadheres to the core. Examples of the liquid form of the proteinaceoussubcoating material include melts and gels. When dry, the subcoatingforms a continuous film over the core and provides a barrier between thecore and enteric coating.

One of the problems we discovered while developing multiparticulatecompositions containing terpene-based active ingredients is that theterpenes sometimes penetrated the conventional subcoating materials andcame in contact with the enteric coating if the temperature was elevated(25 degrees C.-50 degrees C.) or the composition was stored for a longperiod of time. This somewhat reduced the effectiveness of the entericcoating and amount of active ingredient in the core. By using theproteinaceous subcoating, we have substantially eliminated this problem.

The multiparticulate composition is preferably adapted to have acontrolled release profile once it enters the intestines. To treatcertain gastrointestinal disorders, it is highly desirable to avoidreleasing greater than 20% of the total active ingredients in thecomposition over a 2 hour period in a solution with a pH below 4, whichsimulates the liquid environment in the stomach. If the compositionreleases greater than 20% of the active ingredients present, it cancause adverse effects because of the pharmacological action of theterpenes in the stomach. For peppermint oil and L-menthol, for example,this can cause dyspepsia, erosive esophagitis, acid reflux or GERD(gastro-esophageal reflux disease).

Because it is often desirable to be able to ship products innon-refrigerated vehicles and store them for a long period of time, weset out to develop a multiparticulate composition that is stable whenstored at 40 degrees C. and 75% relative humidity, from between 1 day to30 days, and even longer. Using the proteinaceous subcoating allowed usto achieve this objective.

Gelatin typically melts at about 35 degrees C., which is below thenormal human body temperature of about 37 degrees C. Given this, onemight expect that, if a multiparticulate composition, including agelatin subcoating, is heated above 35 degrees C., the subcoating willmelt and release the active ingredients from the core. We observed,however, that gelatin subcoated multiparticulate compositions did notrelease the terpene-based active ingredients from the core even whenheated above 35 degrees C. This is a particularly unexpected result thatprovides numerous advantages.

Because the proteinaceous subcoating prevents volatile terpenecomponents from being released from the core even when heating above themelting point of the proteinaceous material, by applying theproteinaceous subcoating, one does not have to avoid heating thesubcoated cores during processing. One scenario in which this isadvantageous is when the enteric coating is applied. Enteric coatingpolymers have a glass transition temperature (T_(g)) that is often above35 degrees C. After being applied to a core, enteric coated particulatesare preferably heated above T_(g) so that the enteric coating polymercan cure, thereby achieving optimum enteric protection of the core.Thus, using the proteinaceous subcoating between the core and entericcoating allows one to achieve optimum enteric protection withoutreleasing the terpene-based active ingredients from the core.

In certain preferred embodiments of the multiparticulate composition,the subcoating is applied to the core as a gelatin-containing subcoatingsolution. The solvent may be any solvent in which gelatin is soluble,such as water. In a preferred embodiment, the subcoating solutioncomprises about 5% to about 30% w/w gelatin and about 70% to about 95%solvent. When the subcoating solution is allowed to dry around the core,the solvent evaporates, leaving a thin gelatin film that adheres to thecore and forms a barrier between the core and enteric coating.

Surprisingly, in our experiments, drying the core containing theessential oil and water, at about 15 degrees C. to about 25 degrees C.did not result in significant loss of the terpene-based activeingredients as the water was being removed by fluid bed drying.

The enteric coating is applied over the subcoating. In a preferredembodiment, the enteric coating is about 2% w/w to about 35% w/w of theenteric coated particulate. A preferred enteric coating material is amethacrylic acid based material such as a methacrylic acid basedco-polymer. Examples of suitable methacrylic acid based copolymersinclude EUDRAGIT L30D-55 (Evonik Rohm GmbH, Germany) or KOLLICOAT MAE 30DP (BASF SE, Germany). KOLLICOAT MAE 30 DP is a methacrylic acid-ethylacrylate co-polymer. These materials may be combined with othermaterials such as plasticizers for forming an enteric coating solution.In a typical embodiment, the enteric coating solution comprises about 5%w/w to about 35% w/w water, and the enteric-coated driedmultiparticulates contain 0.5% w/w to about 5% w/w plasticizer, about0.05% w/w to about 5% w/w anti-adherent, and about 2% w/w to about 35%w/w methacrylic acid copolymer. By way of example only, a suitableplasticizer is triethyl citrate and a suitable anti-adherent isPLASACRYL T20 (Emerson Resources, Inc., Norristown, Pa.). PLASACRYL T20is an emulsion of anti-tacking agent and plasticizer and contains water,glyceryl monostearate, triethyl citrate and polysorbate 80.

In a particular preferred embodiment of the multiparticulatecomposition, the particulates in the multiparticulate compositioncomprise: (a) a core comprising about 15 w/w to about 35% w/w activeingredient(s), about 40% w/w to about 75% w/w microcrystallinecellulose, and about 2% w/w to about 10% w/w methyl cellulose; (b) agelatin film subcoating over the core; and (c) an enteric coating overthe subcoated core. The gelatin film subcoating is preferably about 3.5%w/w to about 35% w/w of the enteric coated particulates. The entericcoating is preferably about 3.5% w/w to about 35% w/w of the entericcoated particulates.

The enteric-coated particulates may be coated with a finish coat. Thefinish coat is used, for example, to overcome the mucoadhesiveproperties of some enteric coating materials, which make themultiparticulates stick together during processing, storage, ordispensing through a tube for enteral feeding. The finish coat ispreferably a cellulosic derivative such as HPMC (hydroxyl propyl methylcellulose), HPC (hydroxyl propyl cellulose), CMC (carboxy methylcellulose), or another pharmaceutically acceptable finish coatingmaterial. When used, the finish coat is preferably about 1% to 10% w/wof the finished multiparticulate.

The active ingredient release profile in the body can be varied to treatdifferent disorders. By way of example, L-menthol and peppermint oil canbe used to treat a plethora of gastrointestinal disorders such asirritable bowel syndrome, inflammatory bowel disease, and functionaldyspepsia, but it is best to release the active ingredients at a certainpoint in the gastrointestinal treat each disorder.

To treat gastrointestinal disorders associated with irritable bowelsyndrome, the multiparticulate composition is formulated to minimize theamount of active ingredients, such as L-menthol or peppermint oil,released into the stomach and colon, so that most of the activeingredient is released in the small intestine. Preferably, 20% or lessof the active ingredients are released into the stomach and 20% or lessof the active ingredients are released into the colon. Also, the activeingredients are preferably gradually released over the course of about 4to about 8 hours after the multiparticulates pass the pyloric sphincterinto the small intestine in order to deliver the active ingredientslocally in the small intestine. This release profile treatsgastrointestinal disorders by stabilizing the digestive system andalleviating the symptoms associated with disorders such as irritablebowel syndrome.

To treat a gastrointestinal disorder such as functional dyspepsia(classified as a gastro-duodenal disorder), the multiparticulatecomposition is formulated so that the terpene-based active ingredientsare rapidly released, after the multiparticulates pass through thestomach and the pylorus, over the course of about 0 to about 2 hours, inorder to deliver the active ingredients locally to the duodenum sectionof the small intestine to help stabilize the digestive system and/oralleviate the symptoms associated with functional dyspepsia. Preferably,20% or less of the active ingredient(s) is released in the stomach and20% or less of the active ingredient(s) is released in the jejunum andileum sections of the small intestine (which follow the duodenum) andthe colon.

To treat a gastrointestinal disorder such as inflammatory bowel disease,including ulcerative colitis or Crohn's disease), the multiparticulatecomposition is formulated so that the terpene-based active ingredientsare rapidly released, after the multiparticulates pass through thestomach and the small intestine, over the course of about 4 to about 6hours, in order to deliver the active ingredients locally to the colonto attenuate the inflammatory response and/or alleviate the symptomsassociated with inflammatory bowel disease. Preferably, 30% or less ofthe active ingredient(s) is released in the stomach and small intestinegreater than 70% of the active ingredient(s) is released in the first 2hours after the multiparticulates reach the pH of the colon.

A multiparticulate composition particularly geared to treat functionaldyspepsia includes a combination of L-menthol or peppermint oil andcaraway oil. In this embodiment, the core is formulated to contain adisintegrant to facilitate the rapid release of the active ingredientsin the duodenum. Preferred disintegrants include, but are not limited tocroscarmellose sodium, polyvinylpyrrolidone (crospovidone) and/or sodiumstarch glycolate. The amount of disintegrant is preferably about 1% w/wto 20% w/w of the finished multiparticulate. In order to ensure evendistribution of the active ingredient(s), the L-menthol and/orpeppermint oil is dissolved in the caraway oil prior to mixing withexcipients, prior to formation of the cores.

An effective amount is an amount that is sufficient to affect a diseaseor process in the body. A daily dose of a multiparticulate compositioncontaining L-menthol is preferably about 10 mg to about 400 mg ofL-menthol, split into 2 or three doses per day. Each dosage form maycontain between 5 mgs and 140 mgs of L-menthol, more preferably, about80-100 mgs of I-menthol per capsule.

It should be understood that where this disclosure makes reference totreating a gastrointestinal disorder, that the terms “treat,” “treating,or any other variation of the word “treat” include prevention ormanagement of the gastrointestinal disorder.

A daily dose of a multiparticulate composition containing peppermint oilis about 20 mg to about 1200 mgs of peppermint oil, split into 2 orthree doses per day. Each dosage form may contain between 10 mgs and 140mgs of peppermint oil, more preferably, about 90-110 mg of peppermintoil.

A daily dose of a multiparticulate composition containing L-menthol andcaraway oil contains about 15 mg to about 700 mgs of peppermint oil plus15 mg to 500 mgs of caraway oil, split into 2 or three doses per day.Each dosage form may contain between 10 mgs and 70 mgs of L-menthol plus5 mg to 50 mg of caraway oil, more preferably, about 40-50 mg ofL-menthol plus 20-30 mg of caraway oil.

Doses of the multiparticulate composition may be administeredsporadically when needed for treating acute inflammations of thegastrointestinal tract or may be administered as part of a long termregimen for treating GI disorders such as irritable bowel syndrome,functional dyspepsia, gastroparesis or inflammatory bowel disease. Atreatment subject may be a human or animal.

The enteric coated multiparticulates are prepared into a suitablepharmaceutical or medical food dosage form such as a capsule, tablet orsachet, or are mixed with an acidic food vehicle and directly fedthrough a feeding tube. A typical dosage form contains about 400 mg ofthe particulates, but, depending on the desired dosage, this amount maybe adjusted. Acidic food vehicles include citrus juices and foods suchas, for example, apple sauce and apple juice.

The multiparticulate composition is preferably formulated to beadministered enterally, such as orally or through a feeding tube, to ahuman or animal subject to ensure that the subject receives an effectiveamount of terpene-based active ingredients over the course of severalhours after ingestion.

A preferred method of making the multiparticulate composition is nowdescribed. The core is typically prepared by wet granulating the corematerials into a wet mass, extruding the wet mass to form an extrudate,cutting the extrudate into a plurality of core pieces, and spheronizingthe core pieces. The spheronized core pieces are then dried in a dryersuch as a fluid bed dryer to remove most of the water. If desired thedried spheronized cores are then sieved to separate cores of differentsizes.

The dried spheronized cores are then coated with the proteinaceoussubcoating material. One way to apply the subcoating material to thecores is to prepare a subcoating solution and spray the subcoatingsolution onto the cores. There are various conventional methods fordoing this, but the preferred method is Wurster coating or fluid bedcoating (top spray or bottom spray). The subcoating solution issubsequently allowed to dry over the cores, leaving each core coatedwith a thin, continuous proteinaceous film. If desired, the subcoatedcores are sieved to separate them into different sizes.

The enteric coating is then applied to the subcoated cores. One means ofapplying the enteric coating is to spray it onto the subcoated cores.There are various conventional methods for doing this, but the preferredmethod is Wurster coating or fluid bed coating. The enteric coatedparticulates are subsequently dried. During the enteric coating process,the cores are preferably heated in an environment that is about 20degrees C. to about 50 degrees C. to cure the enteric coating materialsabove their T_(g).

A finish coating may be applied over the enteric coated particulates ifdesired. One way to apply the finish coating is to spray it onto theenteric coated cores. There are various conventional methods for doingthis, but the preferred method is Wurster coating or fluid bed coating.

Another method aspect of is a method of treating a gastrointestinaldisorder. This method comprises administering a multiparticulatecomposition including a proteinaceous subcoating between the core andenteric coating to a subject. As mentioned above, there are variousmeans of administration that can be used, including enteraladministration, administration via a feeding tube, and administration infood.

The multiparticulate composition can be enterally administered throughuse of a conventional oral dosage form such as a tablet, caplet,capsule, or sachet, among others.

Another enteral means for administering the multiparticulatecomposition, either orally or via a tube, is as a medical food product.In the medical food product, the multiparticulate composition is blendedwith an acidic food vehicle such as apple juice or another acidicvehicle that prevents premature release of the active ingredients.

Although many of the more specific embodiments we have described includepeppermint oil, L-menthol, and/or caraway oil, one having ordinary skillin the art will understand that the use of a proteinaceous subcoating isgenerally applicable to many other pharmaceutically active terpene-basedactive ingredients because they present the same difficulty; namely,because they are volatile, it is difficult to prepare them in heatstable multiparticulate dosage forms.

EXAMPLES

This section provides specific examples of the multiparticulatecomposition and method aspects. These examples are provided toilluminate certain preferred aspects and embodiments, but the scope isnot limited to what these examples teach.

Example 1: Preparation of a Multiparticulate Composition

The core was prepared using microcrystalline cellulose (MCC)commercially available under the name AVICEL PH 102 (FMC Corp.,Philadelphia, Pa.), methylcellulose commercially available under thename METHOCEL A15LV (Dow Chemical Co., Midland, Mich.), distilledpeppermint oil, and USP purified water.

33.25 kg MCC, 1.75 kg methyl cellulose, and 15 kg peppermint oil wereblended with water to form a wet mass. The wet mass was granulated in ahigh shear granulator. The granulated wet mass was then extruded andspheronized. The spheronized particles were subsequently dried in afluid bed dryer to form uncoated cores. The drying temperature was about16 degrees C.

The uncoated cores were Wurster coated with 37 kg of a subcoatingcomposition containing about 15% acid bone gelatin and 85% USP water anddried.

The subcoated cores were Wurster coated with 31 kg of a 20% w/w entericcoating suspension containing KOLLICOAT MAE 30 DP, PLASACRYL T20,triethyl citrate USP, and purified water USP. The dry solids weight ofamount KOLLICOAT MAE 30 DP was approximately 5.4 kg. The dry solidsweight of triethyl citrate was approximately 0.28 kg. The dry solidsweight of PLASACRYL T20 was approximately 0.5 kg. The enteric coatedcores were then dried at about 40 degrees C.

The enteric coated cores were Wurster coated with 26 kg of a finish coatsolution containing about 10% w/w hydroxyl propyl methyl cellulose and90% water USP and dried at about 40 degrees C.

Example 2: Stability Testing of the Multiparticulate Composition ofExample 1

The multiparticulate composition described in Example 1 was subsequentlytested to ensure that the gelatin subcoating prevented the peppermintoil from evaporating and leaving the core when stored at elevatedtemperatures over a long period of time.

In the first set of experiments, we prepared capsules containing themultiparticulate composition and stored them at 40 degrees C. and 75%relative humidity for four weeks. Each week, we measured the amount ofpeppermint oil in a selection of the capsules. FIG. 1 shows the resultsof this study as a graph of the number of milligrams of L-menthol percapsule as a function of time. The results show that the amount ofL-menthol in the capsules remained more or less constant at about 34 mgduring the four week period. This proves that the gelatin subcoatingmaintains the integrity of the core.

In the second set of experiments, we simulated the gastrointestinalenvironment and measured the dissolution profile of the multiparticulatecomposition to ensure that the enteric coating worked and that almostall of the peppermint oil would be released from the core within about8.5 hours. This was a conventional two stage dissolution study in whichthe sample was placed in an acidic medium (0.1 N HCl) for about twohours and subsequently placed in a neutral medium (pH=6.8) for theremainder of the time.

The results of this experiment are shown in FIG. 2 as the % release ofpeppermint oil, reported as the number of mgs of L-menthol over time.After two hours in the acidic medium, each of the samples tested hadonly released about 10% or less of the peppermint oil, indicating thatthe enteric coating was intact and worked normally. Over the following6.5 hours in the neutral medium, the peppermint oil was graduallyreleased from the core.

Unless otherwise defined, all technical and scientific terms used hereinare intended to have the same meaning as commonly understood in the artto which this pertains and at the time of its filing. Although variousmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the embodiments, suitablemethods and materials are described. The skilled should understand thatthe methods and materials used and described are examples and may not bethe only ones suitable for use.

The specification discloses typical example embodiments, and althoughspecific terms are employed, the terms are used in a descriptive senseonly and not for purposes of limitation. Example embodiments have beendescribed in some detail, but it will be apparent that variousmodifications and changes can be made within the spirit and scope asdescribed in the foregoing specification and in the claims.

That which is claimed is:
 1. A method of making an L-menthol dosageform, the method comprising: forming a wet granulation including anL-menthol source and at least one pharmaceutical excipient; extrudingthe wet granulation into an extrudate; cutting the extrudate intoindividual core pieces; spheronizing the individual core pieces intoindividual spheronized cores; drying the individual spheronized cores toform dried individual spheronized cores; spray coating the driedindividual spheronized cores with a liquid proteinaceous materialforming a film of a proteinaceous material over the dried individualspheronized cores; drying the film of proteinaceous material over thedried individual spheronized cores to form individual subcoated cores;applying an enteric coating over the individual subcoated cores; anddrying the enteric coating over the individual subcoated cores to form aplurality of individual enteric coated cores.
 2. The method of claim 1,wherein the dried film of proteinaceous material is effective tosubstantially prevent L-menthol from leaving the individual entericcoated cores when stored at 40 degrees C. and 75% relative humidity for30 days.
 3. The method of claim 1, further comprising loading theplurality of individual enteric coated cores into a tablet, caplet,capsule, or sachet dosage form.
 4. The method of claim 1, wherein theindividual enteric coated cores are spheroidal and have a diameter of0.1 mm to 3 mm.
 5. The method of claim 1, wherein the L-menthol sourceis L-menthol dissolved in an essential oil.
 6. The method of claim 1,wherein the L-menthol source is peppermint oil.
 7. The method of claim1, wherein the liquid proteinaceous material includes an aqueous gelatinsolution.
 8. The method of claim 1, wherein the liquid proteinaceousmaterial includes a 5% to 35% gelatin aqueous solution.
 9. The method ofclaim 1, wherein the liquid proteinaceous material includes acid bonegelatin.
 10. The method of claim 1, wherein the enteric coating includesa methacrylic acid based material.
 11. The method of claim 1, whereinthe at least one pharmaceutical excipient includes both ofmethylcellulose and microcrystalline cellulose.
 12. The method of claim1, wherein: the L-menthol source is peppermint oil; the at least onepharmaceutical excipient includes both of methylcellulose andmicrocrystalline cellulose; and the liquid proteinaceous materialincludes acid bone gelatin.
 13. The method of claim 1, wherein dryingthe enteric coating includes heating from 20 degrees C. to 50 degrees C.without substantially losing L-menthol.
 14. The method of claim 1,wherein the film of a proteinaceous material is a continuous gelatinfilm that when dried forms a barrier between the core and entericcoating.